小動物臨床前沿（神經(jīng)學(xué)?？?- 上冊）· 腦部疾病
Brain Diseases
New Frontier of Veterinary Medicine
2022 SEP | 總第 12 期
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圖1：組織學(xué)病理診斷為GME的6歲雌性未絕育金毛尋回獵犬的丘腦間連結(jié)的T2W矢狀面(A)和T2W橫斷面(B) 和FLAIR橫斷面(C)。注意T2W
和FLAIR圖像上的彌漫性高強度信號影響到灰質(zhì)(包括皮質(zhì)和深灰質(zhì))和白質(zhì)，累及前腦(顳葉)和腦干(圖片由倫敦大學(xué)皇家獸醫(yī)學(xué)院提供)。
病因不明性腦膜腦脊髓炎(MUO)指的是一組特
發(fā)性、非感染性中樞神經(jīng)系統(tǒng)(CNS)疾病(Talarico
and Schatzberg, 2010; Coates and Jeffery, 2014)。
值得注意的是，術(shù)語MUO與MUA(aetiology病因?qū)W)
和MUE(病因?qū)Wetiology)是同義的，并且所有術(shù)語在
整篇文獻中相互混雜。這組特發(fā)性非感染性腦膜炎
腦脊髓炎(NIME)分為幾個亞型，包括類固醇反應(yīng)性
腦膜炎-動脈炎(steroid responsive meningitis-arteritis，SRMA)、嗜酸性粒細(xì)胞性腦膜腦炎(eosinophilic meningoencephalitis，EME)、肉芽腫性腦膜
腦脊髓炎(granulomatous meningoencephalomyelitis，GME)和壞死性腦炎(necrotizing encephalitis，NE；包括壞死性腦膜腦脊髓炎(necrotizing
meningoencephalomyelitis，NME)和壞死性白質(zhì)腦炎
(necrotizing leucoencephalitis，NLE))。由于SRMA和
EME具有相當(dāng)明顯的診斷特征，因此引入MUO一詞
來涵蓋只能通過組織病理學(xué)證實的NIME三種特定亞
型，包括GME、NME和NLE (Granger et al., 2010;
Talarico and Schatzberg, 2010; Coates and Jeffery,
2014)。目前還沒有關(guān)于犬類MUO的總體發(fā)病率的
統(tǒng)計數(shù)據(jù)，但早期的報告引用了GME在犬所有中樞
神經(jīng)系統(tǒng)疾病中的不一的發(fā)病率5-25%(Braund,
1985; Tipold, 1995)。
通常，MUO的診斷是根據(jù)動物特征、神經(jīng)學(xué)檢
查結(jié)果、磁共振成像(MRI)發(fā)現(xiàn)和腦脊液(CSF)分析
相結(jié)合得出的(Munana and Luttgen, 1998; Adamo
et al., 2007; Granger et al., 2010; Talarico and
Schatzberg, 2010; Coates and Jeffery, 2014)，盡管
這些檢查結(jié)果可能在不同的研究和病患之間存在很
大差異(Wong et al., 2010)。
這組疾病的診斷和治療都使獸醫(yī)面臨挑戰(zhàn)。如
果不開始恰當(dāng)?shù)闹委?，這種疾病被認(rèn)為是致命的
(Munana and Luttgen, 1998; Granger et al., 2010)，
最近的一些研究評估了不同的治療方式和潛在的預(yù)
后因素。
病因?qū)W
MUO 的確切病因?qū)W和病理生理學(xué)目前尚不清
楚，最新的一些理論在最近的一些文獻綜述中進行了
討論 (Coates and Jeffery, 2014)。雖然 MUO 很可能
有多因素發(fā)病機制，但遺傳傾向性和觸發(fā)過度免疫反
應(yīng)的因素的結(jié)合被認(rèn)為是最重要的 (Kipar et al.,
1998; Talarico and Schatzberg, 2010; Flegel et al.,
2011; Coates and Jeffery, 2014)?？梢傻恼T因包括環(huán)
境因素和各類感染性抗原 (Schatzberg et al., 2005;
Greer et al., 2010; Barber et al., 2012)。結(jié) 合 這 組 疾
病對免疫抑制治療的普遍積極反應(yīng)等信息，表明了誘
發(fā) MUO 的因素是免疫介導(dǎo)性疾病 (Wong et al.,
2010)，因此，藥物治療的基石是免疫抑制治療 (Kipar
et al.,1998; Talarico and Schatzberg, 2010; Coates
and Jeffery, 2014)。
臨床表現(xiàn)
中年玩具品種犬和?犬易患 GME (Munana and
Luttgen, 1998; Adamo et al., 2007; Talarico and
Schatzberg, 2010); 而 NE 主要侵襲較小體型的玩具
品種和小型犬，包括巴哥犬、約克夏?、馬爾濟斯犬、
吉娃娃、北京犬、蝴蝶犬、西施犬、圖萊亞爾絨毛犬和
布魯塞爾格里芬犬 (Talarico and Schatzberg, 2010;
Cooper et al., 2014)。然而，任何品種和年齡的犬都
可 能 受 到 侵 襲 (Granger et al., 2010; Coates and
Jeffery, 2014)；最近的一項研究顯示，25% 診斷患有
MUO 的犬是大型犬 (>15kg; Cornelis et al., 2016b)。
通過對 173 例 GME、53 例 MUO 和 69 例 NE 的
數(shù)據(jù)統(tǒng)計分析，發(fā)現(xiàn) GME 和 NE 的年齡分布有顯著差
異；有 NE 的犬主要小于 4 歲，而 GME 的峰值年齡為
4-8 歲 (Granger et al., 2010)。在一組 60 例患 NE 巴哥
犬中 (Levine et al., 2008)，診斷時的中位年齡為 18 個
月。在一組 5 例 NE 的吉娃娃 (Higgins et al., 2008) 中，
診斷時的中位年齡為 5 歲。在巴哥犬中，與深色雄性相
比，淺褐色雌性更常被診斷患有 NME (Greer et al.,
2010)。盡管普遍認(rèn)為 GME 中雌性占多數(shù) (Russo,
1979; Braund, 1985; Bailey and Higgins, 1986; Sorjonen, 1990; Munana and Luttgen, 1998)，在較近期的
研 究 中，雌 雄 比 例 沒 有 統(tǒng) 計 學(xué) 差 異 (Talarico and
Schatzberg, 2010; Granger et al., 2010; Cornelis et al.,
2016a,b)。
曾經(jīng) GME 的組織學(xué)分布有描述三種模式：多灶
型或彌散型、局灶型和眼型 (Cuddon and Smith-Maxie, 1984;Braund,1985; Sorjonen, 1990)。每一種分布型
都與不同的臨床表現(xiàn)有關(guān)，包括多灶型 GME 犬的急性
發(fā)作和快速漸進性發(fā)展，局灶型 GME 犬的發(fā)展更隱匿
或更緩慢漸進性，以及眼型 GME 犬的視覺功能障礙的
急 性 癥 狀 (Braund,1985; Sorjonen,1990; Zarfoss et
al.,2006;Talarico and Schatzberg, 2009; Coates and
Jeffery, 2014)。
神經(jīng)外癥狀很少見，但發(fā)熱偶爾會伴隨于中樞
神經(jīng)系統(tǒng)炎癥(Talarico and Schatzberg, 2010)。常
見的實驗室檢查(血常規(guī)、生化、尿分析)往往在正常
參考范圍內(nèi)(Thomas and Eger, 1989; Sorjonen,
1990; Tipold, 1995)。
在神經(jīng)學(xué)檢查中，疾病定位分類如下：a) GME
以前腦、腦干或多灶型病變?yōu)橹鳎籦) MUO 以多灶型
( 前腦、腦干 ) 或多灶型為主；或 c)NE 以前腦為主
(Granger et al., 2010; Talarico and Schatzberg,
2010; Coates and Jeffery, 2014; Cornelis et al.,
2016a)。與小型犬相比，大型犬更容易出現(xiàn)可識別的
意識狀態(tài)下降 (Cornelis et al., 2016b)。8% 被診斷為
GME 的 犬 表 現(xiàn) 出 提 示 脊 髓 病 的 神 經(jīng) 功 能 缺 陷
(Granger et al., 2010)。脊髓病可定位于脊髓的任何
部位，臨床表現(xiàn)從全身性本體感受性共濟失調(diào)到輕癱
或麻痹；常見發(fā)現(xiàn)有脊髓過度敏感 (Griffin et al.,
2008; Wong et al., 2010; Cornelis et al., 2017a)。
診斷發(fā)現(xiàn)
如前所述，MUO 是一種臨床診斷，可基于動物
特征、神經(jīng)學(xué)檢查結(jié)果、顱內(nèi)橫斷面影像異常和腦脊
液分析獲得 (Munana and Luttgen,1998; Adamo et
al.,2007; Talarico and Schatzberg, 2010; Coates
and Jeffery,2014)。Granger 等人 (2010) 系統(tǒng)性地回
顧了 457 例已發(fā)表的 NIME 病例 ( 包括 MUO、GME
和 NE)，并制定了招募沒有組織病理學(xué)診斷的 MUO
病例的指南。已確定以下四項納入標(biāo)準(zhǔn) : (1) 年齡大
于 6 個月的犬 ; (2) T2W MR 影像上表現(xiàn)為多發(fā)、單
發(fā)或彌漫性軸內(nèi)高強度信號 ; (3) 腦脊液分析表現(xiàn)出
腦脊液細(xì)胞增多，且單核細(xì)胞 / 淋巴細(xì)胞 >50%; (4)
排除特定地理區(qū)域內(nèi)常見的傳染病 (Granger et al.,
2010)。如前所述，只有通過組織病理學(xué)檢查才能獲
得明確診斷 (Uchida et al., 2016)。
橫斷面影像
據(jù)報道，MRI 在檢測大腦異常方面的敏感性為
94.4%，特異性為 95.5%，在腫瘤性和炎癥性疾病的分
類方面也有同樣高度的表現(xiàn)。相比之下，MRI 對腦血
管疾病分類的敏感性僅為 38.9% (Wolff et al., 2012)。
值得注意的是，在一項研究中，多達 7% 的犬 (2/25 例
，一例診斷為 GME，另一例診斷為 MUO) 在 T2W MR
圖 像 中 沒 有 顯 示 異 常 (Talarico and Schatzberg,
2010; Granger et al., 2010)，如果沒有組織病理學(xué)證
據(jù)，可能會導(dǎo)致類似病例不被納入前瞻性研究或回顧
性 研 究。同 樣 在 CT 成 像 方 面，研 究 顯 示 高 達
14%(5/36 例 犬，未 指 定 具 體 診 斷 ) 未 發(fā) 現(xiàn) 異 常
(Granger et al., 2010)?？偟膩碚f，影像學(xué)在識別神經(jīng)
系統(tǒng)檢查懷疑的所有炎癥性異常方面的敏感性仍然
很低 (<60%; Granger et al., 2010)。此外，在一項研究
中，只有 76% 的腦脊液炎性病變病例出現(xiàn) MRI 異常
(19/25 例犬 ; Lamb et al., 2005)。雖然使用橫斷面成
像可能有助于區(qū)分不同類型的特發(fā)性腦膜腦炎
(Talarico and Schatzberg, 2010)，但目前沒有關(guān)于使
用 MRI 鑒別組織病理學(xué)證實的 GME、NME 和 NLE 病
例的信息。
一項研究特別關(guān)注了 11 例組織病理學(xué)證實為
GME 的犬的 MRI 檢查結(jié)果 (Cherubini et al.，2006)。
局灶型、多灶型或彌漫型的 T2W 和 FLAIR 高強度信
號分布于前腦、腦干或小腦 ( 圖 1)。異常散在分布于
灰質(zhì)和白質(zhì)，在 T1 加權(quán) (T1W) 圖像上表現(xiàn)為不同強
度 信號，增強程度不同。T2W 圖像通常提示白質(zhì)內(nèi)血
管源性水腫，腦膜強化通常不明顯，即使有也很輕微
(Cherubini et al., 2006; Talarico and Schatzberg,
2010; Coates and Jeffery, 2014)。MR 影像病變的分
布 ( 位于灰質(zhì)或白質(zhì) ) 與組織病理學(xué)結(jié)果一致
(Cherubini et al., 2006)。
報道的 NME 犬最常見的 MRI 異常是不對稱、多
灶性和位于前腦的病變 ( 更嚴(yán)重的病變位于頂葉和枕
葉 );T2W、FLAIR 高強度信號 ; 通常影響皮質(zhì)灰質(zhì)和
皮質(zhì)下白質(zhì)，在 T1W 增強后圖像上灰質(zhì) / 白質(zhì)界限
喪失，實質(zhì)病變的對比增強程度不同 (Flegel et al.,
2008; Young et al., 2009; Talarico and Schatzberg,
2010; 圖 2）。然而，在一項研究中，分別有 4/18 例和
3/18 例發(fā)現(xiàn)小腦和腦干病變 (Young et al.， 2009)。腦
膜強化也可出現(xiàn)，伴有腫物效應(yīng)和不同程度的腦室增
大 (Coates and Jeffery, 2014)。
在 NLE 中，發(fā)現(xiàn)了多處不對稱的大腦白質(zhì)和腦干
病變 (von Praun et al.， 2006)。這些病變在 T2W 和
FLAIR 上表現(xiàn)為典型的高強度信號，常包括多個囊性
壞死區(qū)域。在兩項已報道的研究中，實質(zhì)異常的對比
度增強很少 (Talarico and Schatzberg, 2010; Coates
and Jeffery, 2014)。第三項研究顯示未見腦膜強化和
腫物效應(yīng)，但伴有不同程度的腦室增大 (Coates 和
Jeffery, 2014; 圖 3)。
已有報道 57 例犬患有不明病因性腦膜脊髓炎，
包括 3 例經(jīng)組織病理學(xué)證實為 GME 的犬 (Cherubini
et al., 2006; Griffin et al., 2008; Wong et al., 2010;
Cornelis et al., 2017a)。57 例中有 36 例使用不同類型
的影像學(xué)檢查結(jié)果。12 例犬單獨進行了（X 線片）脊髓
造影或計算機斷層掃描 (CT) 的脊髓造影；11 例犬未
發(fā)現(xiàn)異常，1 例犬腹側(cè)硬膜外脊髓受壓 (Wong et al.，
2010)。對 25 例犬進行了 MRI 檢查，其中 3 例犬未發(fā)
現(xiàn)異常，6 例犬出現(xiàn)多灶性邊界不清晰的髓內(nèi) T2W 高
強度信號，增強程度不一，在 16 例犬的髓內(nèi) T2W 高
強度信號和 T1W 等強度信號的異常中，脊髓實質(zhì)病
變和 / 或覆蓋腦膜的不同對比度增強 (Cherubini et
al., 2006; Wong et al., 2010; Cornelis et al., 2017a)。
其他成像方式，包括 NME 的正電子發(fā)射斷層掃
描 (PET)， MUO 的氟脫氧葡萄糖 PET (FDG-PET) 和
單體素質(zhì)子磁共振波譜 (1H MRS)，以及 GME 的經(jīng)顱
超聲檢查結(jié)果，被研究作為診斷方式 (Eom et al.,
2008; Kang et al., 2010; Carvalho et al., 2012; Carrera et al., 2016)。然而，需要更大樣本量的進一步研究
來評估這些成像方式的臨床用途。
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